Medical imaging is a well-established technique (in the field of equipments for medical applications), which allows analyzing a body-part of a patient in a substantially non-invasive manner. A specific medical imaging technique is based on the recording of an echo signal that results from the application of ultrasound waves to the body-part. This technique may advantageously be implemented with the administration of an ultrasound contrast agent (UCA) to the patient (for example, consisting of a suspension of phospholipid-stabilized gas-filled microbubbles); as the contrast agent acts as an efficient ultrasound reflector, it enhances the visualization of the vascular system within the body-part where it is present.
Target-specific contrast agents, adapted to reach a specific (biological) target and then remain immobilized thereon, have also been proposed in the last years for facilitating the detection of specific pathologies. Particularly, a target-specific contrast agent is capable of attaching to the corresponding target—such as particular tissues or receptors—by means of a specific interaction therewith; for example, the desired behavior may be achieved by incorporating a target-specific ligand in the formulation of the contrast agent (such as capable of interacting with inflammatory or tumoral tissues). Once the target-specific contrast agent has reached the target remaining immobilized thereon, its detection may allow distinguishing pathologies that would be otherwise difficult to identify.
A problem associated with the target-specific contrast agents is that only a relatively small fraction of the total amount of the administered target-specific contrast agent actually reaches the target and remains immobilized thereon. Most of the target-specific contrast agent continues to circulate, for example, until it is filtered out by the lungs and/or in the liver of the patient. The echo signal that is measured is then the result of different contributions, which are due to the immobilized (target-specific) contrast agent, to the circulating or free-flowing (target-specific) contrast agent and to surrounding tissue. Therefore, it is quite difficult to distinguish the echo signal generated by the immobilized contrast agent from the one generated by the circulating contrast agent and tissue; particularly, it is almost impossible to differentiate the low concentration of the immobilized contrast agent (often consisting of single particles thereof that reach the target individually) from the far higher concentration of the circulating contrast agent.
In the current practice, it is necessary to wait until the circulating contrast agent has completely disappeared (i.e., filtered out) before the immobilized contrast agent can be identified. However, this may require a relatively long time (up to tens of minutes).
A solution for facilitating the detection of the immobilized contrast agent is disclosed in the International patent application No. PCT/EP2006/068305 filed on 9 Nov. 2006 (the entire disclosure of which is herein incorporated by reference). The proposed solution exploits the difference in flow dynamics between the immobilized contrast agent and the circulating contrast agent. Particularly, the echo signal is filtered so as to remove (possibly high-) intensity peaks of short durations caused by the (fast) passage of the circulating contrast agent; the durations of the intensity peaks are shorter than a predefined filtering window. The desired result is achieved by applying a modified version of the Minimum Intensity Projection (Min_IP) algorithm. This allows detecting the immobilized contrast agent with an acceptable degree of accuracy at an early instant after the administration of the target-specific contrast agent to the patient (for example, in the first 2-5 minutes).
Nevertheless, the detection of the target-specific contrast agent that is actually immobilized (i.e., it remains attached to the desired target substantially permanently) is hindered by several disturbing factors.
For example, a problem may be caused by a non-specific interaction of the target-specific contrast agent with a passive target. In this case, the target-specific contrast agent detaches after having been immobilized temporarily, because the non-specific interaction is weaker than the specific-interaction with the intended (active) target; typically, this happens when the passive target includes a receptor similar to the one of the active target, or when the target-specific contrast agent has lost its specificity in the patient (such as under the action of his/her immune system). Anyway, this temporarily-immobilized contrast agent—while it is attached to the passive target—is completely indistinguishable from the permanently-immobilized contrast agent. Therefore, if the body-part is analyzed at an early instant after the administration of the target-specific contrast agent to the patient, any temporarily-immobilized contrast agent leads to an incorrect identification and localization of the desired target (false positives).
Moreover, the above-described solution is unable to discriminate the permanently-immobilized contrast agent from the circulating contrast agent that moves very slowly (such as at the micro-vascular level). Particularly, when the slowly-moving contrast agent remains around the same locations for a period of time longer than the filtering window of the modified Min_IP algorithm, it appears as immobilized at these instants; indeed, the intensity peaks of the echo signal caused by this apparently-immobilized contrast agent are too broad to be removed by the modified Min_IP algorithm.
All of the above may adversely affect the spatial delineation and the quantification of the permanently-immobilized contrast agent, thereby hindering the correct detection of the pathologies of interest.